Systems biology of ageing and longevity
Systems biology of ageing and longevity
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DOI：
10.1098/rstb.2010.0275
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发表时间：
2011-01-12
影响因子：
6.3
通讯作者：
Kirkwood, Thomas B. L.
中科院分区：
文献类型：
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作者：
Kirkwood, Thomas B. L.
老龄化本质上是复杂的，受到多种因果机制的驱动。每一种机制往往都有数据支持，表明它在衰老过程背后的整体细胞和分子途径中起作用。然而，这种作用的重要性通常是有限的。系统生物学方法结合了(i)数据驱动的建模，通常使用功能基因组技术产生的大量数据，以及（ii）假设驱动的实验研究，以一种不同寻常的定量方式调查因果途径并确定其参数值，这使得个体机制的贡献及其相互作用能够更好地理解。并且允许设计明确的实验来测试由这些模型产生的复杂预测。最近关于细胞复制性衰老的研究揭示了线粒体功能障碍、端粒侵蚀和DNA损伤之间的相互作用，这是系统生物学方法在揭示衰老复杂性方面取得成功的一个明显例子。在将（随机）损伤驱动的衰老近似机制网络与影响寿命的更高水平（遗传指定的）信号通路连接起来方面，还存在一个重要挑战。这种联系是由自然选择对衰老和长寿决定因素的作用所决定的。
Ageing is intrinsically complex, being driven by multiple causal mechanisms. Each mechanism tends to be partially supported by data indicating that it has a role in the overall cellular and molecular pathways underlying the ageing process. However, the magnitude of this role is usually modest. The systems biology approach combines (i) data-driven modelling, often using the large volumes of data generated by functional genomics technologies, and (ii) hypothesis-driven experimental studies to investigate causal pathways and identify their parameter values in an unusually quantitative manner, which enables the contributions of individual mechanisms and their interactions to be better understood, and allows for the design of experiments explicitly to test the complex predictions arising from such models. A clear example of the success of the systems biology approach in unravelling the complexity of ageing can be seen in recent studies on cell replicative senescence, revealing interactions between mitochondrial dysfunction, telomere erosion and DNA damage. An important challenge also exists in connecting the network of (random) damage-driven proximate mechanisms of ageing with the higher level (genetically specified) signalling pathways that influence longevity. This connection is informed by actions of natural selection on the determinants of ageing and longevity.